Alzheimer""s disease (AD) is a common neurodegenerative disorder causing dementia. The incidence of AD increases with age (1). The prevalence of dementia rises from 3% at age 65 years to 47% after age 85 years (1). The population of the elderly continues to rise and hence incidence of AD is also expected to rise. The frequency of dementia doubles every 5 years after the age of 60 years. In the United States, the annual cost for AD is estimated to be in excess of $60 billion annually (2, 3). With the rise in numbers of elderly individuals, the prevalence of AD is also expected to rise with concomitant rise in the cost for AD. Development of drugs to delay the progression of AD as well as provide symptomatic treatment of this disorder is thus of paramount importance (1, 2, 3).
In AD there are three major microscopic features that are recognized as the hallmarks of the disease, namely neuritic plaques (NP), neurofibrillary tangles. (NFT) and amyloid angiopathy (AA) (4). In addition, there is widespread cell loss, particularly of cholinergic neurons in the brain (5). Loss of cholinergic cells leads to reduction in the levels of the neurotransmitter acetylcholine, its synthesizing enzyme choline acetyltransferase, as well as its deactivating enzyme acetylcholinesterase (AChE) (5, 6). Reduction of cholinergic neurotransmission leads to some of the symptoms of AD (6).
Although the level of AChE is reduced in AD, the level of the closely related enzyme butyrylcholinesterase (BuChE 3.1.1.8) is increased in AD brains (7). BuChE is found in all the neuropathological lesions associated with AD, namely, NP, NFT and AA (7). Importantly, BuChE is found in NP in brains of patients with AD. BuChE is found in a higher number of plaques in brains of elderly individuals with AD relative to those without AD (8). BuChE in Alzheimer brains requires 10-100 times the concentration of inhibitors to completely inhibit its esterase activity relative to BuChE in normal brains (9). It has been shown that some BuChE inhibitors not only improve cognition in an animal model but also reduce the production of xcex2-amyloid which is one of the principal constituents of neuritic plaques (10).
From a neuropathology perspective, deposition of amyloid and formation of NP is one of the central mechanisms in the evolution of AD (11, 12). However, amyloid plaques are also found in brains of elderly individuals who do not have dementia (13). It has been suggested that the amyloid plaques in individuals without dementia are xe2x80x9cbenignxe2x80x9d and they become xe2x80x9cmalignantxe2x80x9d, causing dementia, when they are transformed into plaques-containing degenerated neurites (13). These plaques are called neuritic plaques (NP). The mechanism of transformation from xe2x80x9cbenignxe2x80x9d to xe2x80x9cmalignantxe2x80x9d plaques is as yet unknown. It has been suggested that BuChE may play a major role in this-transformation based on the observation that BuChE is found predominately in plaques that contain dystrophic neurites and not in plaques without dystrophic neurites (13).
Taken together these observations suggest that in brains of patients with AD there is a significant alteration of the biochemical properties of BuChE that alters its normal regulatory role in the brain thus contributing to the pathology of AD.
Recently, a brain specific serine protease called trypsin IV has been isolated and it is presumed to be involved in APP processing (24). Amyloid precursor protein (APP) is a transmembrane glycoprotein, which possesses a Kunitz-type serine protease inhibitor domain. The APP may be involved in protease regulation in the brain (14, 15). Of particular importance is the fact that abnormally cleaved APP results in the formation of a 40-42 amino acid residue xcex2-amyloid protein fragment. This fragment is the main constituent of NP (16).
The proteolytic sites in APP have been studied extensively (18). There are three known proteolytic sites. The first is the xcex1-secretase site which when cleaved yields a 120 KDa fragment that does not accumulate in amyloid plaques (18). A basic amino acid residue such as arginine at this site is required for cleavage (19). Enzymes that require a basic amino acid residue at the cleavage site of their substrates are serine peptidases, such as trypsin. The second cleavage site, the xcex3-secretase site, cleaves at lys-28 (also a tryptic-site), which is the last amino acid of the extracellular APP domain (20). The third cleavage site, the xcex2-secretase site, occurs at the N-terminus (21). The latter two sites lead to fragments that accumulate in amyloid plaques.
The enzymes that cleave amyloid precursor protein are called xe2x80x9csecretasesxe2x80x9d but they have not been fully identified. (22). It has been observed that a basic amino acid residue is required at some of the sites where APP undergoes proteolytic cleavage (19). Two well-known enzymes that cleave peptides at basic amino acid residue sites are trypsin and carboxypeptidase B (23). Both of these enzymes are mainly recognized as pancreatic enzymes involved in digestion, but trypsin-like serine proteases have been found in the brain and are thought to be involved in APP processing (24, 25, 26, 27). Interestingly, an enzyme with tryptic-like activity is closely associated with BuChE (28, 29). Recent observations that BuChE considerably enhances tryptic activity under normal circumstances (30, 31) and the observations that BuChE, which is found in high levels in NP, has altered biochemical properties, suggests that there may be a loss of regulation of tryptic activity, and other serine peptidase activity, associated with BuChE. This loss of regulation may play a role in abnormal proteolytic processing of APP. Recent evidence suggests that inhibition of BuChE enhances cognitive performance in rats, and that it promotes non-amyloidogenic processing of amyloid precursor protein (10).
Development of molecules that inhibit the activity of BuChE and/or AChE and simultaneously enhance the activity of serine proteases would not only provide symptomatic treatment of AD but would also lead to discovery of drugs that stop the progression of AD.
The present invention provides 2-pyridones that modulate serine hydrolase activity. They inhibit activity of BuChE and or AChE and stimulate activity of trypsin.
More specifically, the present invention provides a compound of formula I: 
or a pharmaceutically acceptable salt thereof;
wherein X is Cxe2x95x90O, Cxe2x95x90S or CH2;
R3, R4 and R6 are each independently selected from the group consisting of hydrogen, (C1-C12)alkyl, substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, substituted (C3-C8)cycloalkyl, (C2-C12)alkenyl, substituted (C2-C12)alkenyl, (C2-C12)alkynyl, substituted (C2-C12)alkynyl, (C6-C14)aryl, substituted (C6-C14)aryl, (C1-C12)alkyl (C6-C14)aryl, substituted (C1-C12)alkyl (C6-C14)aryl, (C6-C14)aryl (C1-C12)alkyl, substituted (C6-C14)aryl (C1-C12)alkyl, (C6-C14)aryl (C2-C12)alkenyl, substituted (C6-C14)aryl (C2-C12)alkenyl, (C6-C14)aryl (C2-C12)alkynyl, substituted (C6-C14)aryl (C2-C12)alkynyl, (C2-C14)heterocyclic, substituted (C2-C14)heterocyclic, trifluoromethyl, halogen, cyano and nitro;
xe2x80x94S(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2ORxe2x80x2 and xe2x80x94S(O)2NHRxe2x80x2, wherein each Rxe2x80x2 is independently (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl or (C6-C14)aryl;
xe2x80x94C(O)Rxe2x80x3, wherein Rxe2x80x3 is selected from the group consisting of hydrogen, (C1-C12)alkyl, substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, substituted (C3-C8)cycloalkyl, (C1-C12)alkoxy, (C1-C12)alkylamino, (C2-C12)alkenyl, substituted (C2-C12)alkenyl, (C2-C12)alkynyl, substituted (C2-C12)alkynyl, (C6-C14)aryl, substituted (C6-C14)aryl, (C6-C14)aryloxy, (C6-C14)arylamino, (C1-C12)alkyl (C6-C14)aryl, substituted (C1-C12)alkyl (C6-C14)aryl, (C6-C14)aryl (C1-C12)alkyl, substituted (C6-C14)aryl (C1-C12)alkyl, (C6-C14)aryl (C2-C12)alkenyl, substituted (C6-C14)aryl (C2-C12)alkenyl, (C6-C14)aryl (C2-C12)alkynyl, substituted (C6-C14)aryl (C2-C12)alkynyl, (C2-C14)heterocyclic, substituted (C2-C14)heterocyclic and trifluoromethyl;
xe2x80x94ORxe2x80x2xe2x80x3 and xe2x80x94NRxe2x80x2xe2x80x32, wherein each Rxe2x80x2xe2x80x3 is independently selected from hydrogen, (C1-C12)alkyl, substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, substituted (C3-C8)cycloalkyl, (C2-C12)alkenyl, substituted (C2-C12)alkenyl, (C2-C12)alkynyl, substituted (C2-C12)alkynyl, (C6-C14)aryl, substituted (C6-C14)aryl, (C1-C12)alkyl (C6-C14)aryl, substituted (C1-C12)alkyl (C6-C14)aryl, (C6-C14)aryl (C1-C12)alkyl, substituted (C6-C14)aryl (C1-C12)alkyl, (C6-C14)aryl (C2-C12)alkenyl, substituted (C6-C14)aryl (C2-C12)alkenyl, (C6-C14)aryl (C2-C12)alkynyl, substituted (C6-C14)aryl (C2-C12)alkynyl, (C6-C14)aroyl, substituted (C6-C14)aroyl, (C2-C14)heterocyclic, substituted (C2-C14)heterocyclic, (C1-C12)acyl and trifluoromethyl;
xe2x80x94SRxe2x80x3xe2x80x3, wherein Rxe2x80x3xe2x80x3 is selected from the group consisting of hydrogen, (C1-C12)alkyl, substituted (C1-C12)alkyl, (C2-C12)alkenyl, substituted (C2-C12)alkenyl, (C2-C12)alkynyl, substituted (C2-C12)alkynyl, (C6-C14)aryl, substituted (C6-C14)aryl, (C1-C12)alkyl (C6-C14)aryl, substituted (C1-C12)alkyl (C6-C14)aryl, (C6-C14)aryl (C1-C12)alkyl, substituted (C6-C14)aryl (C1-C12)alkyl, (C6-C14)aryl (C2-C12)alkenyl, substituted (C6-C14)aryl (C2-C12)alkenyl, (C6-C14)aryl (C2-C12)alkynyl, substituted (C6-C14)aryl (C2-C12)alkynyl, (C2-C14)heterocyclic, substituted (C2-C14)heterocyclic and trifluoromethyl; and
xe2x80x94SiRxe2x80x2xe2x80x3xe2x80x33, wherein Rxe2x80x2xe2x80x3xe2x80x3 is selected from (C1-C12)alkyl or (C6-C14)aryl; and
R7 and R8 are each independently selected from the group consisting of hydrogen, (C1-C12)alkyl, substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, substituted (C3-C8)cycloalkyl, (C2-C12)alkenyl, substituted (C2-C12)alkenyl, (C2-C12)alkynyl, substituted (C2-C12)alkynyl, (C6-C14)aryl, substituted (C6-C14)aryl, (C1-C12)alkyl (C6-C14)aryl, substituted (C1-C12)alkyl (C6-C14)aryl, (C6-C14)aryl (C1-C12)alkyl, substituted (C6-C14)aryl (C1-C12)alkyl, (C6-C14)aryl (C2-C12)alkenyl, substituted (C6-C14)aryl (C2-C12)alkenyl, (C6-C14)aryl (C2-C12)alkynyl, substituted (C6-C14)aryl (C2-C12)alkynyl, (C2-C14)heterocyclic, substituted (C2-C14)heterocyclic and trifluoromethyl; or
xe2x80x94NR7R8 forms a (C2-C14)heterocyclic or substituted (C2-C14)heterocyclic group;
wherein the substituted groups listed above are substituted with one or more substituents selected from the group consisting of hydroxy, (C1-C4)alkoxy, (C6-C14)aryl, (C2-C14)heterocyclic, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbamate, sulfonyl and sulfonamide,; and
the heterocyclic group contains at least one atom, preferably two, selected from oxygen, nitrogen and sulfur.
The present invention also provides a pharmaceutical composition comprising a compound of formula I disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. Preferably the pharmaceutical composition of the invention is for the modulation of an activity of a serine hydrolase.
Compounds of the formula I, while depicted herein in their xe2x80x9cketoxe2x80x9d tautomeric form, can also exist in their corresponding xe2x80x9cenolxe2x80x9d tautomeric form. 